The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia
The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia
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DOI：
10.1158/2326-6066.cir-17-0212
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发表时间：
2018-02-01
影响因子：
10.1
通讯作者：
Salih, Helmut Rainer
中科院分区：
文献类型：
--
作者：
Nuebling, Tina;Schumacher, Carla Emilia;Salih, Helmut Rainer
TNF受体家族成员OX 40促进T细胞的活化和增殖，从而促进调节该免疫检查点以增强抗肿瘤免疫的努力。除T细胞外，NK细胞是第二种细胞毒性淋巴细胞亚群，有助于抗肿瘤免疫，特别是在白血病中。因此，这些细胞正在通过多种方法进行癌症治疗的临床评估，例如过继转移离体扩增的多克隆NK细胞（pNKC）。在这里，我们分析了OX 40及其配体（OX 40 L）是否以及如何影响NK细胞功能和抗白血病反应性。我们报告说，OX 40表达的白血病原始细胞在相当大的比例的急性髓细胞白血病（AML）患者和OX 40可以，刺激后与激动剂OX 40抗体，介导增殖和释放的细胞因子，作为生长和生存因子的白血病细胞。我们还表明，pNKC差异表达OX 40 L，这取决于用于其生成的协议。OX 40 L信号传导促进NK细胞活化、细胞因子产生和细胞毒性，并且OX 40-OX 40 L相互作用的破坏损害pNKC对原代AML细胞的反应性。总之，我们的数据暗示OX 40/OX 40 L在AML的疾病病理生理学和NK细胞免疫监视中。我们的研究结果表明，OX 40 OX 40 L受体-配体系统在其他免疫细胞亚群和恶性细胞中的作用，在开发OX 40靶向癌症免疫治疗方法时应予以考虑。(C)2018年AACR。
The TNF receptor family member OX40 promotes activation and proliferation of T cells, which fuels efforts to modulate this immune checkpoint to reinforce antitumor immunity. Besides T cells, NK cells are a second cytotoxic lymphocyte subset that contributes to antitumor immunity, particularly in leukemia. Accordingly, these cells are being clinically evaluated for cancer treatment through multiple approaches, such as adoptive transfer of ex vivo expanded polyclonal NK cells (pNKC). Here, we analyzed whether and how OX40 and its ligand (OX40L) influence NK-cell function and antileukemia reactivity. We report that OX40 is expressed on leukemic blasts in a substantial percentage of patients with acute myeloid leukemia (AML) and that OX40 can, after stimulation with agonistic OX40 antibodies, mediate proliferation and release of cytokines that act as growth and survival factors for the leukemic cells. We also demonstrate that pNKC differentially express OX40L, depending on the protocol used for their generation. OX40L signaling promoted NK-cell activation, cytokine production, and cytotoxicity, and disruption of OX40-OX40L interaction impaired pNKC reactivity against primary AML cells. Together, our data implicate OX40/OX40L in disease pathophysiology of AML and in NK-cell immunosurveillance. Our findings indicate that effects of the OX40OX40L receptor-ligand system in other immune cell subsets and also malignant cells should be taken into account when developing OX40-targeted approaches for cancer immunotherapy. (C) 2018 AACR.